Mefloquine (Larium) is the most effective malaria prophylaxis currently available, yet its general use remains highly controversial in Europe, especially in England. Neuropsycological disorders among users including depression, vivid dreams, fatigue, headache and insomnia are well documented in British medical journals as well as in the general media. In contrast, American medical journals have paid relatively little attention to side effects of the drug even though it is used more widely in the United States than in England. The Center for Disease Control (CDC) recommends mefloquine for travelers in malarial regions with a minimum a warning about possible neurological side effects. The few American observational studies have been conducted either on military personnel or Peace Corps Volunteers, not typical tourists. In contrast, data gathered in England have been based on the personal experiences of business and leisure travelers.

Both in letters and articles, American researchers have not convincingly defended the CDC position that neurological side effects of mefloquine are rare. Although mefloquine is likely the most effective malarial prophylaxis available today, patients should be counseled concerning their options and possible, not rare, side effects. Patient compliance with prophylaxis regimens outside of a military setting is disturbingly poor, possibly in part due to side effects of the drugs. Both European and American doctors should be vigilant that the information they provide to patients regarding mefloquine is accurate. This information should include a review of the dangers of malaria balanced with a prophylaxis regimen that the patient will adhere to armed with full knowledge of possible side effects.

The Need for Malaria Prophylaxis:

Malaria is a common and potentially fatal disease; there are between 300 to 500 million cases worldwide each year and 1.5-2.7 million deaths annually. Every year 25 to 30 million people from non-tropical countries visit malarial regions of the world, often for extended periods of time. Of these, approximately 30 thousand North American and European travelers contract malaria annually. Even when travelers are treated for malaria, mortality can be as high as 10% and even higher (20%) for cerebral malaria. Studies have shown that travelers who do not take malaria prophylaxis have a high risk of contracting malaria, especially in sub-Saharan Africa. Thus there is a demonstrated need for an effective preventive drug regimen for non-immune travelers when they travel to countries where the disease is common.

Mefloquine has been used to treat some cases of malaria since 1980 and has been used as a malaria prophylaxis since 1986. Since then mefloquine has been prescribed to over 12 million travelers worldwide. Data gathered in the early 1990's confirmed that mefloquine was both safe and effective, however more recent studies in England have challenged the safety of the drug and suggested that serious neurological side effects may make mefloquine difficult for some people to take.

Mefloquine Studies: United States

Hans Lobel et al argue in a December 1997 issue of JAMA, that mefloquine is safe and effective with rare side effects. Lobel bases his argument largely on two observational studies, one done on US soldiers in Somalia and a second on Peace Corps volunteers serving in West Africa. Both studies compared mefloquine with other malaria prophylaxes and found mefloquine to be the more effective drug and with few side effects. The basis for this conclusion however, lies largely with the characteristics of the populations chosen for the study. The populations in these two studies are not representative of typical travelers; both groups are relatively young, and in the case of the Somalia study, almost entirely male.

The Somalia study was conducted from December 1992 though May 1993 and included all documented malarial cases among the approximately 30 thousand US troops who served in Somalia during that time. Interestingly, the authors neglect to provide an age profile of the population in their demographic description; however given the demographics of the American military and the nature of the operation, it is safe to assume most were male and most were relatively young. This scenario is problematic given that previous studies have shown that men tolerate mefloquine better than women do.

All military units were given doxycycline, an alternative malaria prophylaxis, or mefloquine in approximately equal numbers during the first weeks of the Somalia operation. After 6 weeks everyone was switched to mefloquine for reasons of uniformity and soldiers found it easier to remember to take the weekly dosage of mefloquine as opposed to daily doxycycline. Possible side effects due to prophylaxis were studied through a survey of one Marine unit (n=499.) 94% of them returned the survey, evidence of the strict discipline that characterizes this population. Interestingly, investigations into malaria cases among doxycycline users revealed that the soldiers contracted malaria because they forgot to take the daily dosage, not because the drug itself was ineffective. Therefore the conclusion that mefloquine is more effective is specific to the social characteristics of the military population studied; this group of soldiers found the weekly mefloquine dosage easier to remember. The possibility of different effects of the prophylaxis on women and men was not addressed in the study (probably could not be given the likely demographics). There is a significant chance that women who take birth control pills may find the doxycycline dosage regimen easier to comply with than male soldiers because they are accustomed to adhering to a daily dosage regimen.

The study on Peace Corps volunteers was conducted between October 1989 and May 1992 in six West African nations, all with uniformly high malarial rates. Age and gender demographics were not specified. Since most volunteers join the Peace Corps right after graduating from college, it is again a relatively young population. A breakdown of the numbers of men and women in the study was also missing from the demographics. Gender stratification to adjust for possible confounding is not mentioned in the methods section, a possible serious flaw in the analysis.

Both a dose response study of mefloquine and a comparison of mefloquine and chloroquine with proguanil and chloroquine with pyrimethamine-sulfadoxine regimens were compared in the study. Doxycycline, the current alternative to mefloquine, was not included in the study. A weekly dosage of mefloquine was found to be the most effective of the three regimens in the study. In addition, a cohort of 152 volunteers who had used mefloquine exclusively were monitored for a year to test side effects over time. Only seven (0.9%) requested a different prophylaxis because of severe side effects. The authors concluded that mefloquine is safe for long-term use with rare side effects.

The study of Peace Corps volunteers was published before observational studies conducted in England found significant neurological side effects; however individual reports of neurological problems with the drug were surfacing in the European media. The authors of the Peace Corps study dismiss these complaints in their discussion by denying there is evidence of a causal relationship as indicated by their data. They cite the stresses of traveling and being in a new environment as possibilities for individual neurological disorders. Further, they stress the importance of a uniform prophylaxis regimen so as not to confuse members of the medical profession, hardly a justifiable concern in light of new data! Medical professionals should be aware of prophylactic options so as to prescribe the one most suitable for the patient. Careful consideration of all the evidence available is more important for doctors prescribing medication than the possible confusion that could result.

The only further monitoring concerning mefloquine the authors suggest focuses on the possible development of mefloquine-resistant strains of malaria. Any further questions concerning the safety of the drug they consider minor, especially in light of its effectiveness and the severe morbidity and mortality issues associated with contracting malaria. Lobel et al also dismiss possible neurological side effects by citing that depression in the general US population is 16 times higher than among mefloquine users. Such a comparison the worst kind of ecological fallacy; it is not possible to make a valid comparison between a highly selective study population and the general population.

The lax attitude on the part of the researchers toward a relatively new drug, which has primarily been tested on specific social groups, is dangerous. Both studies fail to address and control for gender and age, possible significant confounders. The study of Peace Corps volunteers is dated in that it did not compare mefloquine with doxycycline; chloroquine regimens are rarely recommended today because many regions of the world have chloroquine-resistant malaria. A new study that takes into account both gender and age demographics and includes a mix of business and leisure travelers is necessary.

Mefloquine Studies: England

In response to the growing debate in England regarding the safety of mefloquine, Croft et al conducted a systematic review of mefloquine randomized trials published in the British Medical Journal in 1997. Ten studies met their qualifications for inclusion. One placebo controlled trial found mefloquine effective however four placebo controlled trials found that mefloquine had serious neurological side effects. Of the five trials that compared mefloquine with other malaria prophylaxes, researchers found higher withdrawal rates in mefloquine users. This finding was used as evidence that the side effects of the drug were causing people to stop taking it. The authors' ultimate conclusion was that mefloquine should only be used in specific regions with high rates of chloroquine-resistant malaria and little access to medical care. Mefloquine should thus not be the standard malaria prophylactic treatment as suggested by Lobel et al.

Croft's conclusions, however, were not universally accepted in England. Several letters to BMJ cited two major flaws with Croft's conclusions. First, mefloquine withdrawal is not evidence that the drug has neurological side effects. There is no evidence of a causal relationship; there are many reasons for a person to decide to stop taking a drug. Secondly, all malaria prophylactic drugs have side effects, therefore a comparison between a placebo and mefloquine is problematic. Croft's response is not particularly convincing; she emphasizes the need for a field trial of tourists and business travelers in order to resolve the debate. True such a trial is necessary, however this explanation does not resolve methodological problems upon which she based her conclusion.

The mefloquine debate confusion:

While the basis of the conclusions in Croft's review is problematic, a closer look at one of the trials included in his review and more recent data indicate that the debate concerning neurological side effects attributed to mefloquine remains unresolved. A telephone and postal survey conducted in 1996 found that a significant proportion of mefloquine users experienced neurological side effects. The survey included British travelers recently returned from trips during which they took mefloquine or proguanil plus chloroquine. Twenty-seven percent of mefloquine users indicated they experienced neurological side effects (0.7% "disabling") compared with only 16% (0.09% "disabling") of the chloroquine plus users. The authors recommend mefloquine only in high-malaria and chloroquine-resistant areas. While again, no age or gender demographics are provided, this study of typical travelers presents a strong argument that some neurological effects are relatively common.

The debate in England rages on. More recently in 1998, BMJ reported an increase in malaria cases in England, which coincided with a reduction in the use of mefloquine. Many people simply stopped taking any prophylaxis when they traveled. The resulting cost of treatment for those that contract malaria as a result is a concern for the National Health Service. An examination of malaria cases indicated many patients received, "misleading or inadequate advice from health care professionals."

Confusion in the healthcare profession regarding malaria prophylaxis is also common in the United States. According to the CDC, there were 4685 reported cases of malaria among US civilian travelers from 1992-2001. Nineteen percent took an inappropriate prophylaxis (such as chloroquine in a chloroquine resistant region) and in 56% of the cases the travelers took no prophylaxis at all. This suggests a lack of knowledge regarding the severity of malaria among the traveling population and significant misinformation in the medical community that prescribed the wrong medication.

The use of qualitative evidence:

Interestingly the incidence of serious neurological side effects was similar in both the US (0.9%) and British studies (0.7%). The British study went a step further to capture any neurological side effects, while US studies did far less analysis in this area. Furthermore, British researchers used qualitative data collection and analysis to carefully document the symptoms of the 0.7% of people who experienced severe side effects. The use of qualitative data to investigate the small group had significant effects on the British general population. Logically numbers should convince both researchers and the general public alike that a drug is safe. Personal accounts, however rare, can be a powerful influence on person's decision concerning whether they would choose to take a particular medication. The American public and research community was not influence by publicized personal experiences with mefloquine. In contrast, British medical journals and the general media publicized several case studies including moving accounts of personal experiences with the side effects of mefloquine. The following is one patient's experience:

I continued the treatment even though my hair began to fall out and my eyesight seemed to be getting worse…Throughout the night…my dreams were vivid, and I was convinced I was going to die. The next day the flowers were larger and brighter and the stones on the way to work were hairy. I was on a trip I hadn't planned. Fortunately, that morning 4 issues of the BMJ arrived; in one of them was an article on prophylaxis against malaria. Doxycycline is readily available..so I started a daily dose. I now feel well and energetic and am sleeping, and my appetite has returned-I feel normal.

Multiple accounts similar to this one are not only cited in BMJ, but also in the general British media. Watchdog, a BBC television program, has featured, "graphic accounts of severe, sometimes long lasting, largely neuro-psychiatric, symptoms they attribute to mefloquine." This is probably at least partially responsible for the alarm concerning the drug in England. The fact that it is the most effective defense against contracting malaria was lost in the scare. Indeed mefloquine, "which in most people's minds has a terrifying reputation," became rather demonized. Many travelers arrived at the dangerous conclusion that the risks of contracting malaria were less than taking mefloquine. Thus incidence of malaria cases in England began to rise. Qualitative data is important for identifying who is at risk for side effects. However both researchers and the media should be prudent concerning how they release such information and try and lessen the tendency to sensationalize the evidence.

The US has failed to personalize the debate in this form of qualitative research both the general media in its medical journals. The general public is thus not effected by personal accounts however it is disturbing that the 27% of travelers in the British study who reported some neurological side effects remains unacknowledged in the American medical community. Dismissing these accounts as anecdotal is not defendable especially in light of the flaws in the quantitative methods in both the Somalia and West African studies. The British, however, have yet come up with the kind of large-scale study that offers answers to the concerns raised in their qualitative research.

Conclusions and the need for further research:

To date, I could find no evidence of a comprehensive observational study using a typical travel population. The possibility of gender bias was mentioned in only one article and even then as barely a footnote. For reasons unknown to me, none of the major articles stratified the study population by age.

The CDC continues to promote mefloquine as the best line of defense against malaria, specifically stating that side effects are rare and minor. This information is misleading in light of the 27% of travelers who reported side effects in the British study. More information is needed on who these 27% of people are; who is more likely to experience side effects, men or women, older or younger people.

Additionally the two studies upon which the CDC information is based have serious design flaws that questions their validity when applied to a larger, more diverse population. While the British survey of travelers provided a more accurate picture of a typical travel population, it too suffered from the same flaws concerning gender and age analysis. In addition, sensationalizing the qualitative data concerning severe side effects of only 0.7% of mefloquine users demonized the drug in England. As a result both mefloquine's effectiveness and the dangers of malaria were severely downplayed.

The information on the CDC website declares that doxycycline and a newer drug Malarone should be considered only as alternatives to mefloquine. Once more information is available on who is at risk for side effects due to mefloquine both doctors and their patients can make a more informed choice concerning which prophylaxis is most appropriate and effective for them.

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My wife and I have taken Larium on three trips over the past 4 years while traveling in malaria areas for a total of eight months. While in the Peace Corps in Ethiopia (1962-64) we took Aralin (sp?) for two years.

Although we have friends who have told us of adverse effects of Larium, the only time either of us has had an adverse reaction to Larium was one bad dream after taking Larium just before bedtime.

When taking Larium with food in the morning, we have never had an adverse reaction. We also havn't contracted malaria.

I took Larium/Mephaloquine for the first 6 months while I was a Peace Corps Volunteer in The Gambia ('97-'99). I experienced intense, vivid nightmares in which creatures and people were chasing and trying to kill me. I also experienced insomnia and lack of appetite. I switched to doxycycline. The symptoms stopped completely. I didn't have any difficulty remembering to take the daily dosage of doxy, because I have a thyroid condition(hypothyroidism, or Hashimoto's disease) and had to take a daily dosage of synthroid, anyway. I just combined the two. Some people with Hypothyroidism have a tendency to experience depression. It would be interesting what results one might obtain by conducting a study researching the side effects of Larium with possible links to people with thyroid disorders. Michelle Elsbury RPCV The Gambia '97-'99

As a Peace Corps volunteer in Malawi 1993-1996, I took Larium for my entire 3 yrs. of service. I experienced no problems, never skipped a dose and am grateful that I did not get malaria due to this effective drug.

How can such a powerful drug get such wide-spread, and mandatory use with such sloppy, inadequate and controversal research? Appaling, and we call medicine "science based." MALARIA KILLS, but the long conflicting Larium saga certainly leaves much to be desired. I speak from experience with both Malaria and Larium.

Excellent scientific article. Was it mentioned that the studies done with the military and the Peace Corps Volunteers is flawed because both groups are REQUIRED to take a prophylaxis (if serving in an area where malaria is a danger? I served in Africa. If the Peace Corps Medical Officer found out you weren't taking your Mefloquine, you would be sent home. So, most people just quit taking it. I would bet the same is true of military personnel. When asked if they had any side effects... of course they didn't have any side effects, because they hadn't taken the drug!!!

Lariam is a Pandora's box. I'm not against protecting myself from Malaria. Malaria is bad. My anger is based on the fact that I wasn't given the opportunity to make an informed decision on what I was taking. There were no warnings given. We were under the impression that all those wild dreams was just part of the trip.

I took Lariam during throughout my service as a PC volunteer. I had vivid dreams/nightmares early on, but nothing serious. I started having panic attacks 1 year later on Mondays, the day I took Lariam. I asked to switch to another prophylaxis and was denied by the PC Medical Officer.

There was a fellow volunteer who had seizures from taking Lariam (didn't have them before) and had to go to another country where malaria is not endemic.

I was wondering if there is a age/weight requirement or recommendation as metabolism differences could be a factor. Are there any studies done or in the works on this?

The mefliquin was good. I throughly enjoyed my dreams when on it, and got malaria twice anyway. In the area I lived I was not the only volunteer who regularly took their mefliquin to come down with malaria. I know people from my stage who had rough times while on it and so they switched to doxi. All stated they felt much better after the switch. None-the-less these days back in the states I sometimes wish for 2 or 3 larium pills so I could get back to those kick ass vivid dreams for a week or so. Maybe it is just time to go back to Africa.

I left Peace Corps after 4 months because i was suffering from such intense anxiety and depression. On a few occasions I could not differentiate between my dreams and reality. I switched to doxy two weeks before I came home but three weeks later I am still struggling with the anxiety and depression. During my service I was told by doctors that my symptoms were in the minority. It doesn't offer me much comfort considering the number of people who commit suicide are in the minority also. It doesn't affect everyone but it does greatly affect some. Just be aware which group you fall into.

I took lariam while in the peace corps and have suffered paranoia, anxiety attacks, suicidal ideation (luckily I have not had this for over a year), but I still suffer from paranoia and anxiety. It's awfull. I don't feel I was well informed about the drug, thus I was unable to make informed decisions about what I was mixing with this drug. Had we been better informed those of us that did have side-effects could have realized it was the Lariam, and not us. Instead I was in silence for years thinking I was crazy. I would still like to see justice served, but I am skeptical. Sincerely, Melody

I took it in West Africa for a year. It might be the combination of all the vaccines mixed with the Larium. Whatever the case, there is a hightened state of anxiety without a sense of peace. The effects last at least a year afterwards.

I graduated from pharmacy school in dec 2005, went to africa, came back sick and was treated with mefloquine.Ever since I've been having panick attacks, cant sleep, cant eat, feeling spaced out and robotic, almost like someone with no feelings or care about anything.At first everone thought it was in my mind, but then I found horrifying articles on line about this drug. I am truly praying to god for this nightmare to be over soon. DO people ever fully recover from this and how? Angie

I just returned from Congo. I went there direct from Russia and Larium is the only anti malarial available in Russia> The russian Doc prescribed me a tab a day! for 3 days then 1 a week. After about 4 days i was totally out of my mind with anxiety and paranoia and couldnt sleep. I have taken larium twice before without noticing the effects so i think it was the dosage. I have stopped taking it but it has left me with some feeling of irritation in the urethra. Looking back i think i remember this from the previous occasions i took it - but i cant find anyone else who records this effect.

I am posted in Africa for 2 years. I started taking Lariam just over 2 months ago. I had no problem with the vivid dreams which I was informed about by my doctor. When I first arrived I failed to listen to several of my co-workers that they had stopped taking Lariam because they suffered from severe depression. These past few weeks really have turned my life up side down with negitive thought, depression, no motivation, anxiety, paranoia, unsociable and some times suicidal thoughts. This is hard to deal with when normally I am so positive and happy. I have stopped taking them recently and pray to get back to my normal sane self. I wish I had listened to my friends!

I took Lariam for treatment of what I thought was malaria after a trip to Africa. The next day I experienced the most horrific nausea, ataxia, abdominal pain and a sense of impending doom. I hope all my symptoms resolve. And I must mention insomnia. I have always been able to fall asleep right after I get to bed. Today I couldn't. I took Lariam yesterday. That is why I am up trying to research more about the drug and found all this info. This drug should be taken off the shelves!!!

Another Peace Corps volunteer here. I took Mefloquine for my first year in a West African country. At first the dreams were kind of cool; very vivid, colorful. And you could definitely tell which were the normal dreams and which were the Mefloquine-induced ones. But after a year, the dreams became much more violent. Usually me killing lots of people in a very violent way, or someone else doing the killing. Finally, I came down with pretty bad insomnia. I switched to Doxy and was 99% better, although I can attest to the fact that side effects can linger, in my case I still had the occasional Mefloquine dream two years after stopping the treatment; as I said, you can always tell the difference. However, I didn't come down with malaria. I think Mefloquine is a very effective drug and probably worth the side effects in most people. The problem is not with the drug, but with its administration in the Peace Corps. I knew at least 3 other people who had very strange symptoms, who were generally misdiagnosed, one with diabetes and one with migraines. But after getting sent home for medical reasons, their symptoms went away. The medical office, when confronted with a sudden onset of any strange symptoms should consider the link to Mefloquine as the FIRST POSSIBLE EXPLANATION. This would probably save a lot of people a lot of needless suffering. While not as effective (supposedly), I never got sick on Doxy, nor did anyone else I know who took it regularly, although one girl who took Mefloquine (religiously) did come down with malaria. This is anecdotal, of course.

I think this was the medication I was taking in the PC in the 80s in West Africa when I had a single panic attack. I was sent home and kicked out of the Peace Corps. Never had another panic attack since. The PCMO experience in DC was very negative, non supportive and hurtful.

I served an LDS mission in the Ivory Coast and took Larium. I did experience the very vivid dreams and some anxiety. I stopped taking the drug and contracted malaria twice. I know that several other missionaries stopped taking Larium due to the psychological side effects and were given another drug, not sure what. The drug seemed to bother some of the female missionaries much more than the males. Several had a loss of hair, though to be a side effect of Larium.

I am a 31 y.o. male RPCV from Niger, West Africa, 1998/1999. While taking the mefloquine/lariam medication during my service, I experienced severe anxiety and panic attacks as well as the vivid night terrors, including dreams of violence. The dreams were fun at first but then got progressively worse as time went on. It was not until about a year into my service that the anxiety and panic attacks were onset. After switching to doxycycline, my symptoms were lessened, but still present and severe enough that medivac was necessary. I'd also like to point out that I took my medication religiously, and still contracted malaria. In any case,while on medivac, I went through the rigmarole of CAT scans, MRIs, EKGs, etc. In 2000, after my Peace Corps experience,I was diagnosed with Panic Disorder, for which I took medication and visited many different doctors over about a year or so. I was completely disfunctional in society for about 12-14 months. No doctors, psychiatrists, psychologists, etc. ever attributed my condition to mefloquine/lariam. It was determined that I was suffering from some PTSD for several traumatic events that happened while I was in service. Albeit, this could be true, I have never been fully convinced that the mefloquine/lariam did not play a significant role in my panic attacks and any other anxiety type symptoms (palpitations, ringing of ears, shortness of breath, sweaty palms, etc), I had them all. I am happy to report that it is now 2008 and I have since been functional in society once again, and at times I remember this seeming unachievable. In addition, since these episodes, I have completed a Masters of Science degree, am working professionally, bought a house, and I am now about to even get married. I have not needed anxiety medication, other than occasionally clonazapam (As Needed), for about 7 years now. So there is hope, for those of you who do not see the light at the end of the tunnel. I will never take lariam again, but thats not to say it isn't the correct medication for some people. Like they say, it is anectotal. In all honesty, always remember that being in a third world country and in a foreign land and presenting our body and mind with physical and mental challenges that we could have never previously fathom can cause severe anxiety and night terrors in itself, even if we try to convince ourselves otherwise. I hope this post was helpful to some.

I am a current PCV in Tanzania. I have been taking mefloqine for two months and have experienced no adverse effects. The first week I had a single scary dream but I refuse to automatically attribute it to the mefloquine.

I do agree that the Peace Corps could do a better job of addressing volunteer concerns about the drug.

Personal opinion starts here. I have noticed that nearly all of the personal anecdotes about long-term mefloquine use come from either military or Peace Corps. I think it needs to be said that both of these groups lead unusally stressful lives, and that should be taken into account when trying to decide what caused mental disturbances.

It looks like the FDA finally put the "black box label" on it. About time. Why not just ban it? Hoffman-Laroche got to use as as guinea pigs. I'm a toxicologist and don't get me started on the biochemistry of this drug, which I knew nothing about 14 years ago. Anyway. A step in the right direction. I was the 2008 Post, RPCV from Niger West Africa.

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